Project Summary/Abstract Acute graft-versus-host disease (aGVHD) is a principal contributor to transplant related mortality (TRM), and develops in approximately 60-80% of recipients receiving unrelated donor hematopoietic stem cell transplantation (HSCT) despite standard immunosuppressive prophylaxis. Thus, novel GVHD prophylaxis treatments which successfully attenuate aGVHD and related complications such as infection are urgently needed. In addition, an important function of allogeneic HSCT is to use donor T cells to eliminate allogeneic leukemia cells, this is called the graft-versus-leukemia (GVL). However, current prophylaxis and treatment of GVHD is based on general immunosuppression, which causes high risk of infection and cause significant mortality, while contributing to leukemia relapse by reducing GVL. The ultimate goal of this research project is to further the clinical development of a novel drug candidate for the prophylactic treatment of aGVHD in leukemia patients undergoing allogeneic myeloablative HSCT. In preclinical testing in murine models, the drug candidate, CD24Fc, has been shown to significantly reduce GVHD severity and improve in survival while preserving GVL, making it an ideal drug for prophylaxis of GVHD in leukemia patients. The activity associated with GHVD reduction and GVL preservation is strongly supported by in vitro data that describes the mechanism of action of the CD24Fc drug product. CD24Fc has been demonstrated to be safe in healthy human subjects in a Phase I clinical trial and the current project, a Phase IIa clinical trial, aims to provide the first toxicity/safety, pharmacokinetics, pharmacodynamics and biological activity data for CD24Fc in human HSCT transplantation patients. These data demonstrate that we have more than reached the milestones typically set for phase I SBIR grant, and thus qualify us for phase II direct SBIR application. The proposed Phase IIa trial is a randomized double blind single ascending dose trial comprised of 3 dosing cohorts of 8 patients (3:1 treatment:placebo), for a total planned enrollment of 24 subjects. The clinical trial will have two specific aims addressed by different phases: specific aim I will determine the safety and tolerability of CD24Fc in a single ascending dose-escalation study, and define the recommended Phase II dose (or Maximum Tolerated Dose) for prophylaxis of GVHD in a large Phase IIb expansion trial; and specific aim II will assess the pharmacokinetics and in-human activity of CD24Fc in leukemia and myeloid dysplasia syndrome patients receiving HSCT. CD24Fc will be administered to patients on a background of standard of care prophylaxis comprising a calcineurin inhibitor and methotrexate to maximize patient safety. The proposed study represents a major milestone necessary not only for the development of the novel immunomodulating drug for a GVHD, but also for commercialization effort of the company.